ClinVar Genomic variation as it relates to human health

PVS1, PS4_moderate, PM2, PM3

In families where this variant has been associated with autosomal recessive inheritance, c. 1471+1 G>A has been identified as heterozygous variant in unaffected parents (Meyer-Kleine et al., 1995; Ronstedt et al., 2015); however, information about families with myotonia who only harbor the c.1471+1 G>A variant is limited.; Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24452722, 25065301, 27614575, 18337100, 31589614, 33304817, 8533761, 26502825)

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 447052). Disruption of this splice site has been observed in individual(s) with myotonia congenita (PMID: 8533761, 22094069, 22521272, 24349310, 27614575). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs375596425, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This sequence change affects a donor splice site in intron 13 of the CLCN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125).

The heterozygous c.1471+1G>A variant in CLNC1 was identified by our study, in the compound heterozygous state along with a variant of uncertain significance (NC_000007.14:g.143339511G>A), in one individual with congenital myotonia. This individual also carried a variant of uncertain significance (NC_000007.14:g.143339511G>A), however the phase of these variants are unknown at this time. The c.1471+1G>A variant in CLNC1 has been previously reported in 12 unrelated individuals with autosomal recessive myotonia congenita (PMID: 33304817, PMID: 25438602, PMID: 22094069, PMID: 27614575, PMID: 31544778, PMID: 25065301, PMID: 22521272, PMID: 24349310, PMID: 8533761) but has been identified in 0.001% (1/68044) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs375596425). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 447052) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. Of these 12 previously reported affected unrelated individuals, 1 was a homozygote (PMID: 27614575), six were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 22094069, ClinVar Variation ID: 289967; PMID: 27614575, PMID: 24349310, PMID: 8533761, ClinVar Variation ID: 17545), one was a compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 25438602, ClinVar Variation ID: 17545; ), and two were compound heterozygotes who carried variants of uncertain significance in trans (PMID: 31544778, ClinVar Variation ID: 209138, 1013567; PMID: 25065301), which increases the likelihood that the c.1471+1G>A variant is pathogenic. RT-PCR analysis performed on RNA from affected tissue showed evidence of exon skipping of exon 13 (PMID: 17932099). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function is an established disease mechanism of autosomal recessive myotonia congenita. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive myotonia congenita. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PS3_Supporting, PM3_VeryStrong (Richards 2015).

The c.1471+1G>A (p.?) variant was found in a heterozygous state in 1 Slovak patient with Myotonia congenita, who carried another two Likely pathogenic variants in cis: [c.905A>G; c.1295C>A]. The c.1471+1G>A variant is listed as a disease-causing in the HGMD database (CS951379). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.0000315.